Cerebral perfusion is maintained constant over a wide range of systemic pressures via counter-regulatory changes in cerebrovascular resistance. Effective "autoregulation" maintains cerebral blood flow via cerebrovascular resistance changes that fully counteract sustained changes in arterial pressure. This mechanism is critical to neurophysiologic health since too little flow could cause ischemia whereas too much could raise intracranial pressure. Beat-by-beat assessment of cerebral blood flow velocity has shown that cerebral flow is regulated not just over minutes and hours but also on shorter time scales of only a few beats. Pressure changes are damped over periods as short as 15 seconds (i.e., ~0.07 Hz) and this dampening is progressively greater over longer time periods. Despite the critical importance of this autoregulatory capacity, there is very little information on the underlying physiologic mechanisms. The specific aims of the proposed research are to explore the roles of alpha- adrenergicsympatheticvasoconstriction,endothelial-derivednitricoxide,andvascularmyogenicresponsesinthe short-term regulation of cerebral blood flow. We hypothesize that the sympathetic role in cerebral flow regulation is predominant at higher frequencies (i.e., faster pressure changes), the endothelial nitric oxide role plays a small role in regulation at lower frequencies (i.e., slower pressure changes), and the vascular myogenic role is a predominanteffectorofautoregulationattheselowerfrequencies.Morecompleteunderstandingofthecontrollers for cerebral autoregulation will allow identification of deficits in a number of pathophysiologic conditions. One especially relevant example is traumatic brain injury(TBI)that results in post-concussion symptoms. A likely culprit for these symptoms is cerebral autoregulatory dysfunction. Therefore, as an additional aim, we will characterize cerebral blood flow autoregulation in symptomatic and asymptomatic TBI and evaluate the association between cerebral blow flow autoregulation and symptoms in TBI. We hypothesize that cerebrovascular autoregulatory function under sympathetic control (shorter time scales ) will be impaired in TBI patients with symptoms, whereas autoregulatory function under nitric oxide and myogenic control (longer time scales) will remain intact. To test our hypotheses, we will generate systemic pressure changes across a range of frequencies that encompass cerebral blood flow autoregulation in humans, from 10 second fluctuations down to as low as 50 second fluctuations. We will assess the relationship between cerebral blood flow and systemic blood pressure via both linear and non-linear analyses and determine the effects of sympathetic alpha-adrenergic blockade, of nitric oxide synthase blockade, and of calcium channel blockade on the autoregulatory capacity of the cerebral vasculature. In addition,as a check to determine how these responses differ from non-cerebral arterial beds, we will assess the relation between brachial blood flow and systemic blood pressure under these same conditions. From this work, we will be able construct a comprehensive picture of the physiology that underlies cerebral autoregulation in humans and test the pathophysiology that may underlie symptoms common to traumatic brain injury. PUBLIC RELEVANCE: Maintaining brain flow constant over a wide range of blood pressures is critical to health since too little flow could cause brain death whereas too much could raise the pressure on the brain. Despite the fact that this function of the brain blood vessels is of critical importance, there is very little information on the underlying mechanisms. Therefore, the proposed research will explore the roles of various control systems in the regulation of brain blood flow and provide information on their contribution to alterations in brain blood flow that may underlie symptoms after traumatic brain injury.